Non-Standard Neutrino Interactions from a Triplet Seesaw Model

We investigate non-standard neutrino interactions (NSIs) in the triplet seesaw model featuring non-trivial correlations between NSI parameters and neutrino masses and mixing parameters. We show that sizable NSIs can be generated as a consequence of a nearly degenerate neutrino mass spectrum. Thus, these NSIs could lead to quite significant signals of lepton flavor violating decays such as \mu^- \to e^- \nu_e anti\nu_\mu and \mu^+ \to e^+ anti\nu_e \nu_\mu at a future neutrino factory, effects adding to the uncertainty in determination of the Earth matter density profile, as well as characteristic patterns of the doubly charged Higgs decays observable at the Large Hadron Collider.Comment: 4 pages, 3 figures and 1 table; v2: minor corrections, Sect. IV revise

Preclinical development of a humanized chimeric antigen receptor against B-cell maturation antigen for multiple myeloma

Multiple myeloma is a prevalent and incurable disease, despite the development of new and effective drugs. The recent development of chimeric antigen receptor (CAR)T cells has shown impressive results in the treatment of patients with relapsed or refractory hematologic B-cell malignancies. In recent years, B-cell maturation antigen (BCMA) has appeared as a promising antigen to target using a variety of immunotherapy treatments, including CART cells, for patients with multiple myeloma. To this end, we generated clinical-grade murine CART cells directed against BCMA, named ARI2m cells. Having demonstrated its efficacy, and in an attempt to avoid the immune rejection of CART cells by the patient, the single chain variable fragment was humanized, creating ARI2h cells. ARI2h cells showed comparable in vitro and in vivo efficacy to that of ARI2m cells, and superiority in cases of high tumor burden disease. In terms of inflammatory response, ARI2h cells produced less tumor necrosis factor-αand were associated with a milder in vivo toxicity profile. Large-scale expansion of both ARI2m and ARI2h cells was efficiently conducted following Good Manufacturing Practice guidelines, obtaining the target CART-cell dose required for treatment of multiple myeloma patients. Moreover, we demonstrated that soluble BCMA and BCMA released in vesicles both affect CAR-BCMA activity. In summary, this study sets the bases for the implementation of a clinical trial (EudraCT code: 2019-001472-11) to study the efficacy of ARI2h-cell treatment for patients with multiple myeloma

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor

Background: Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. Methods: TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. Results: We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. Conclusion: This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies

Galilean quantum gravity with cosmological constant and the extended q-Heisenberg algebra

We define a theory of Galilean gravity in 2+1 dimensions with cosmological constant as a Chern-Simons gauge theory of the doubly-extended Newton-Hooke group, extending our previous study of classical and quantum gravity in 2+1 dimensions in the Galilean limit. We exhibit an r-matrix which is compatible with our Chern-Simons action (in a sense to be defined) and show that the associated bi-algebra structure of the Newton-Hooke Lie algebra is that of the classical double of the extended Heisenberg algebra. We deduce that, in the quantisation of the theory according to the combinatorial quantisation programme, much of the quantum theory is determined by the quantum double of the extended q-deformed Heisenberg algebra.Comment: 22 page

Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken

Soluble fibres (non-starch polysaccharides, NSP) from edible plants but particularly plantain banana (Musa spp.), have been shown in vitro and ex vivo to prevent various enteric pathogens from adhering to, or translocating across, the human intestinal epithelium, a property that we have termed contrabiotic. Here we report that dietary plantain fibre prevents invasion of the chicken intestinal mucosa by Salmonella. In vivo experiments were performed with chicks fed from hatch on a pellet diet containing soluble plantain NSP (0 to 200 mg/d) and orally infected with S.Typhimurium 4/74 at 8 d of age. Birds were sacrificed 3, 6 and 10 d post-infection. Bacteria were enumerated from liver, spleen and caecal contents. In vitro studies were performed using chicken caecal crypts and porcine intestinal epithelial cells infected with Salmonella enterica serovars following pre-treatment separately with soluble plantain NSP and acidic or neutral polysaccharide fractions of plantain NSP, each compared with saline vehicle. Bacterial adherence and invasion were assessed by gentamicin protection assay. In vivo dietary supplementation with plantain NSP 50 mg/d reduced invasion by S.Typhimurium, as reflected by viable bacterial counts from splenic tissue, by 98.9% (95% CI, 98.1–99.7; P<0.0001). In vitro studies confirmed that plantain NSP (5–10 mg/ml) inhibited adhesion of S.Typhimurium 4/74 to a porcine epithelial cell-line (73% mean inhibition (95% CI, 64–81); P<0.001) and to primary chick caecal crypts (82% mean inhibition (95% CI, 75–90); P<0.001). Adherence inhibition was shown to be mediated via an effect on the epithelial cells and Ussing chamber experiments with ex-vivo human ileal mucosa showed that this effect was associated with increased short circuit current but no change in electrical resistance. The inhibitory activity of plantain NSP lay mainly within the acidic/pectic (homogalacturonan-rich) component. Supplementation of chick feed with plantain NSP was well tolerated and shows promise as a simple approach for reducing invasive salmonellosis

Testing of cryogenic photomultiplier tubes for the MicroBooNE experiment

The MicroBooNE detector, to be located on axis in the Booster Neutrino Beamline (BNB) at the Fermi National Accelerator Laboratory (Fermilab), consists of two main components: a large liquid argon time projection chamber (LArTPC), and a light collection system. Thirty-two 8-inch diameter Hamamatsu R5912-02mod cryogenic photomultiplier tubes (PMTs) will detect the scintillation light generated in the liquid argon (LAr). This article first describes the MicroBooNE PMT performance test procedures, including how the light collection system functions in the detector, and the design of the PMT base. The design of the cryogenic test stand is then discussed, and finally the results of the cryogenic tests are reported

Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families

Model-free classification of X-ray scattering signals applied to image segmentation

In most cases, the analysis of small-angle and wide-angle X-ray scattering (SAXS and WAXS, respectively) requires a theoretical model to describe the sample’s scattering, complicating the interpretation of the scattering resulting from complex heterogeneous samples. This is the reason why, in general, the analysis of a large number of scattering patterns, such as are generated by time- resolved and scanning methods, remains challenging. Here, a model-free classification method to separate SAXS/WAXS signals on the basis of their inflection points is introduced and demonstrated. This article focuses on the segmentation of scanning SAXS/WAXS maps for which each pixel corresponds to an azimuthally integrated scattering curve. In such a way, the sample composition distribution can be segmented through signal classification without applying a model or previous sample knowledge. Dimensionality reduction and clustering algorithms are employed to classify SAXS/WAXS signals according to their similarity. The number of clusters, i.e. the main sample regions detected by SAXS/WAXS signal similarity, is automatically estimated. From each cluster, a main representative SAXS/WAXS signal is extracted to uncover the spatial distribution of the mixtures of phases that form the sample. As examples of applications, a mudrock sample and two breast tissue lesions are segmented

Large underground, liquid based detectors for astro-particle physics in Europe: scientific case and prospects

This document reports on a series of experimental and theoretical studies conducted to assess the astro-particle physics potential of three future large-scale particle detectors proposed in Europe as next generation underground observatories. The proposed apparatus employ three different and, to some extent, complementary detection techniques: GLACIER (liquid Argon TPC), LENA (liquid scintillator) and MEMPHYS (\WC), based on the use of large mass of liquids as active detection media. The results of these studies are presented along with a critical discussion of the performance attainable by the three proposed approaches coupled to existing or planned underground laboratories, in relation to open and outstanding physics issues such as the search for matter instability, the detection of astrophysical- and geo-neutrinos and to the possible use of these detectors in future high-intensity neutrino beams.Comment: 50 pages, 26 figure

Geographic distribution of the V1016G knockdown resistance mutation in aedes albopictus. A warning bell for Europe

Background: Colonization of large part of Europe by the Asian tiger mosquito Aedes albopictus is causing autochthonous transmission of chikungunya and dengue exotic arboviruses. While pyrethroids are recommended only to reduce/limit transmission, they are widely implemented to reduce biting nuisance and to control agricultural pests, increasing the risk of insurgence of resistance mechanisms. Worryingly, pyrethroid resistance (with mortality &lt; 70%) was recently reported in Ae. albopictus populations from Italy and Spain and associated with the V1016G point mutation in the voltage-sensitive sodium channel gene conferring knockdown resistance (kdr). Genotyping pyrethroid resistance-associated kdr mutations in field mosquito samples represents a powerful approach to detect early signs of resistance without the need for carrying out phenotypic bioassays which require availability of live mosquitoes, dedicated facilities and appropriate expertise.Methods: Here we report results on the PCR-genotyping of the V1016G mutation in 2530 Ae. albopictus specimens from 69 sampling sites in 19 European countries.Results: The mutation was identified in 12 sites from nine countries (with allele frequencies ranging from 1 to 8%), mostly distributed in two geographical clusters. The western cluster includes Mediterranean coastal sites from Italy, France and Malta as well as single sites from both Spain and Switzerland. The eastern cluster includes sites on both sides of the Black Sea in Bulgaria, Turkey and Georgia as well as one site from Romania. These results are consistent with genomic data showing high connectivity and close genetic relationship among West European populations and a major barrier to gene flow between West European and Balkan populations.Conclusions: The results of this first effort to map kdr mutations in Ae. albopictus on a continental scale show a widespread presence of the V1016G allele in Europe, although at lower frequencies than those previously reported from Italy. This represents a wake-up call for mosquito surveillance programs in Europe to include PCR-genotyping of pyrethroid resistance alleles, as well as phenotypic resistance assessments, in their routine activities